4-imino-3-phenyl-2-oxoimidazolidine-1-acetonitriles



United States Patent 3,463,787 4-IMINO-3-PHENYL-2-0XOIMIDAZOLIDINE- l-ACETONITRILES Frederick K. Kirchner, Bethlehem, and Andrew W. Zalay,

Albany, N.Y., assignors to Sterling Drug Inc., New York, N.Y., a corporation of Delaware No Drawing. Continuation-impart of application Ser. No. 524,829, Feb. 3, 1966. This application May 31, 1968, Ser. No. 733,232

Int. Cl. C07d 49/30; A61k 27/00 US. Cl. 260309.7 3 Claims ABSTRACT OF THE DISCLOSURE 4-imino-3-phenyl-2-oxoimidazolidine 1 acetonitriles having utility as antiinflammatory agents are obtained by interacting iminodiacetonitrile with phenyl isocyanates.

This application is a continuation-in-part of prior copending application Ser. No. 524,829, filed Feb. 3, 1966, now US. Patent 3,429,911, issued Feb. 25, 1969.

This invention relates to compositions of matter classified in the art of chemistry as substituted imidazolidines.

The invention sought to be patented, in its composition aspect, is described as residing in the concept of a chemical compound having a molecular structure in which there is attached to a 4-imino-2-oxoimidazolidine nucleus a phenyl radical or its hereinafter disclosed equivalent in the 3-position and a cyanomethyl group in the 1-position.

The tangible embodiments of the composition aspect of the invention possess the inherent general physical properties of being white crystalline solids; are substantially insoluble in water; and are soluble in polar solvents, such as lower aliphatic alcohols. Examination of compounds produced according to the hereinafter described process reveals, upon infrared spectrographic and nuclear magnetic resonance spectroscopic analysis, spectral data confirming the molecular structure hereinbefore set forth. The aforementioned physical characteristics, taken together with the nature of the starting materials and the mode of synthesis, positively confirm the structure of the compositions sought to be patented.

The tangible embodiments of the invention possess the inherent applied use characteristics of exerting an antiinflammatory effect in animals, as evidenced by laboratory evaluation.

The manner and process of making and using the invention will now be generally described so as to enable a person skilled in the art of chemistry to make and use the same.

Iminodiacetonitraile is a known compound and is useful for conducting the reaction with an isocyanate RNCO, R representing the hereinbefore described phenyl radical. By such reaction there is produced the 4-imino-3-R-2- oxoimidazolidine-l-acetonitriles of the invention.

The physical embodiments of our concept are made by reacting iminodiacetonitrile with phenyl isocyanate bearing the phenyl moiety it is desired to have appear in the 3-position of the composition of the invention. Although the reaction may be carried out from ambient temperature to about 100 C. it is generally preferred to carry out the reaction above room temperature at about 60- 70 C. When the reaction is carried out in the presence of an inert organic solvent, the temperature is generally maintained at about the reflux temperature. The reaction is generally completed in one hour. The proportion of the reactants is preferably equimolar.

The reaction proceeds via the appropriate intermediate ureas RNHCON(CH CN) which cyclize to the products of the invention. Although in certain instances the ureas can be isolated they cyclize upon standing or by suspen- 3,463,787 Patented Aug. 26, 1969 "ice sion in an inert solvent. The inventors contemplate the intermediate ureas as within the scope of their invention.

The best mode contemplated by the inventors of carrying out their invention will now be set forth as follows:

Example 1 To a solution of 9.5 g. of iminodiacetonitrile in ml. of tetrahydrofuran was added 18.8 g. of 3,5-dichlorophenyl isocyanate and the mixture refluxed for one-half hour. Addition of benzene caused the separation of a solid which was collected by filtration to give 208 g. of l-bis (cyanomethyl) -3-(3,5-dichlorophenyl)urea of the formula CHaON NHCON 1 CHnGN and which melted at 103-105 C.

Recrystallization from a tetrahydrofuran-benzene mixture, either by sequential heating and cooling, or at ambient temperature or at 0 C. gave the cyclized product 3-(3,5-dichlorophenyl)-4-imino-2 oxoirnidazolidine 1- acetonitrile of the formula 01 HN=ooH,

N NCHiON o 1 II and which melted at 147-149 C.

Example 2 HN=CCH:

NGHzCN and which melted at 186-187 C.

The intermediate l-bis(cyanomethyl)-3-(4-nitrophenyl)-urea of the formula CHaCN ohm-Grin o o N/ CHzCN was not isolated but rather was cyclized during recrystallization.

Example 3 (a) A solution of 38 g. of iminodiacetonitrile in 100 ml. of tetrahydrofuran was treated with 30.8 g. of 4- chlorophenyl isocyanate in ml. of tetrahydrofuran and the mixture heated on a steam bath fo one-half hour. Benzene (200 ml.) was added and the mixture slightly concentrated. The solid which separated on cooling was collected by filtration and dried to give l-bis- (cyanomethyl)-3-(4-chlorophenyl)urea of the formula CHzCN (HQ-NH 0 ON \CH2CN and which melted at -96 C.

The urea was converted to the cyclized product either by suspension in toluene followed by refluxing or by standing at ambient temperature for several weeks. The 3 (4 chlorophenyl) 4 imino-2-oxoimidazolidine-lacetonitrile thus obtained melted at 152-157 C. and had the formula and which melted at 151-153" C.

(c) Following the same procedure but using 2.5 ml. of 4-chlorophenyl isocyanate rather than methyl isocyanate there was obtained 7.3 g. of 3-(4-chlorophenyl)- 4 (4-chlorophenylcarbamoylimino)-2-oxoimidazolidinel-acetonitrile having the formula NCHQCN and which melted at 2l2214 C.

(d) The imino group of 3-(4-chlorophenyl)-4-imino- 2-oxoimidazolidine-l-acetonitrile was hydrolyzed in 1 N hydrochloric acid at room temperature to give 3-(4-chlorophenyl) 2,4-dioxoimidazolidine-l-acetonitrile having the formula and which melted at 164165 C.

Example 4 Proceeding in a manner similar to that described above in Example 3(a), except the isolation of the intermediate, i.e., l-bis(cyanomethyl)-3-phenylurea was omitted, and using 19 g. of iminodiacetonitrile and 22 g. of phenyl isocyanate there was obtained 7.7 g. of 4-imino-3-phenyl-2- oxoimidazolidine-l-acetonitrile of the formula and which melted at IOU-104 C.

Example 5 Proceeding in a manner similar to that described above in Example 3(a), except the isolation of the intermediate, i.e., 1-bis(cyanomethyl)-3-(4-methoxyphenyl)- urea was omitted, and using 19 g. of iminodiacetonitrile and 30 g. of 4-methoxyphenyl isocyanate there was obtained 33.7 g. of 3-(4-methoxyphenyl)-4-imino2-oxoimidazolidine-l-acetonitrile, of the formula and which melted at 131133 C.

Example 6 Proceeding in a manner similar to that described above in Example 3(a), except the isolation of the intermediate, i.e., 1 bis(cyanomethyl)-3-(3-chlorophenyl)urea was omitted, and using 19 g. of iminodiacetontrile and 30.8 g. of 3-chlorophenyl isocyanate there was obtained 18.9 g. of 3 (3 chlorophenyl) 4-imino-2-oxoimidazolidine-l-acetonitrile, of the formula HN=C CH3 NCHzCN l Q 1 l and which melted at 122-123" C.

Example 7 Proceeding in a manner similar to that described above in Example 3(a), except the isolation of the intermediate, i.e., 1 bis(cyanomethyl) 3 (2-chlorophenyl)urea was omitted, and using 19 g. of iminodiacetonitrile and 30.8 g. of 2-chlorophenyl isocyanate there was obtained 16 g. of the desired 3-(2-chlorophenyl)-4-imino-2-oxoimidazolidine-l-acetonitrile having the formula Q1. lam...

O 1 ll and which melted at 157-15 8 C.

Example 8 Proceeding in a manner similar to that described above in Example 3(a), except the isolation of the intermediate, i.e., l bis(cyanomethyl)-3-(3,4-dichlorophenyl)- urea was omitted, and using 9.5 g. of iminodiacetonitrile and 18.8 g. of 3,4-dichlorophenyl isocyanate there was obtained 19 g. of the desired 3-(3,4-dichlorophenyl)- 4 imino 2 oxoimidazolidine 1 acetonitrile having the formula QQIL and which melted at 138 141 C.

Example 9 Proceeding in a manner similar to that described above in Example 3(a), except the isolation of the intermediate, i.e., 1 bis(cyanomethyl) 3-(4-bromophenyl)urea was omitted, and using 9.5 g. of iminodiacetonitrile and 20 g. of 4-bromophenyl isocyanate there was obtained 15 g. of the desired 3 (4 bromophenyl)4-imino-2-oxoimidazolidine having the formula l Q K NCHzCN and which melted at 163165 C.

Example Proceeding in a manner similar to that described above in Example 3(a), except the isolation of the intermediate, i.e. l-bis(cyanomethyl)-3-(2,4-dichlorophenyl)urea was omitted, and using 9.5 g. of iminodiacetonitrile and 18.8 g. of 2,4-dich1orophenyl isocyanate there was obtained 13.4 g. of the desired 3-(2,4-dichlorophenyl)-4-imino-2- oxoimidazolidine-l-acetonitrile having the formula o1- 1L lLCHaCN and which melted at 112-115 C.

Example 11 Proceeding in a manner similar to that described above in Example 3(a) and using 6.6 g. of iminodiacetonitrile and 9.6 g. of 4-fluorophenyl isocyanate there was obtained 8.3 g. of 1-bis(cyanomethyl)-3-(4-fluorophenyl)urea having the formula GHzON OHaCN and which melted at 85-87 C.

The urea was dissolved in hot toluene and the mixture cooled; the precipitate formed was collected and dried to give 5 g. of 3-(4-fluorophenyl)-4-imino-2-oxoimidazolidine-l-acetonitrile having the formula HN=CCH and which melted at 151-152 C.

Example 12 Proceeding in a manner similar to that described above in Example 3 (a), except the isolation of the intermediate, i.e. 1-bis(cyanomethyl)-3-(4-tolyl)urea was omitted and using 9.5 g. of iminodiacetonitrile and 13.3 g. of 4-tolyl isocyanate there was obtained 21 g. of 4-imino-2-oxo-3- (4-to1y1)imidazolidine-l-acetonitrile having the formula and which melted at 166167 C.

Example 13 Proceeding in a manner similar to that described above in Example 3(a), except the isolation of the intermediate, i.e. 1-bis(cyanomethyl)-3-(3-trifluoromethylphenyl)urea was omitted, and using 9.5 g. of iminodiacetonitrile and 17.5 g. of 3-trifluoromethylphenyl isocyanate there was obtained 28.8 g. of 4imino-3-(3-trifluoromethylphenyl)- 2-oxoimidazolidine-l-acetonitrile having the formula Fa g and which melted at 86--87 C.

Example 14 Proceeding in a manner similar to that descirbed above in Example 3(a), except the islation of the intermediate, i.e. 1-bis(cyanomethyl)-3-(4 methylmercaptophenyl) 6 urea was omitted, and using 9.5 g. of iminodiacetonitrile and 16.5 g. of 4-methylmercaptophenyl isocyanate there was obtained 12 g. of 4-imino-3-(4-methylmercaptophenyl)- 2-oxoimidazo1idine-l-acetonitrile having the formula and which melted at -87 C.

The intermediate 4-methylmercaptophenyl isocyanate was prepared by a reaction of 87.8 g. of 4-methylmercaptoaniline and a saturated solution of phosgene in chlorobenzene to give 74 g. of 4-methylmercaptopheny1isocyanate, B.P. 117118 C./8 mm.

Example 15 NCHaCN Proceeding in a manner similar to that described above in Example 3(a), except the isolation of the intermediate, i.e. 1-bis(cyanomethyl)-3 (4 acetypheny1)urea was omitted, and using 9.5 g. of iminodiacetonitrile and 16.1 g. of 4-acetylphenyl isocyanate there was obtained 19.5 g. of 3-(4-acetylphenyl)-4imino 2 oxoimidazolidine-lacetonitrile having the formula HN=CCH NOHzCN and which melted at 97-98 C.

Example 16 Proceeding in a manner similar to that descirbed above in Example 3 (a), except that the isolation of the intermediate, i.e. 1-bis(cyanomethyl)3-(4-cyanophenyl)urea was omitted, and using 9.5 g. of iminodiacetonitrile and 14.4 g. of 4-cyanophenyl isocyanate there was obtained 16 g. of 3-(4-cyanophenyD-4-imino 2 oxoimidazolidine-lacetonitrile having the formula NO-Q-IL r romou and which melted at 209-210 C.

Example 17 Proceeding in a manner similar tothat described above in Example 3 (a), except that the isolation of the intermediate, i.e. 1-bis(cyanomethyl)-3 (4 trifluorome-thylphenyDurea was omitted, and using 9.5 g. of iminodiacetonitrile and 17.5 g. of 4-trifluoromethylphenyl isocyanate there was obtained 15 g. of 4-imino-3-(4-trifiuoromethylphenyl)-2-oxoimidazolidine-l-acetonitrile having the formula cuts are, without limiting the generality of the foregoing lower alkylphenyl, e.g. methylphenyl, ethylphenyl, isopropylphenyl, or any other analogous lower alkylphenyl radical, halophenyl, e.g. chlorophenyl, bromophenyl, iodophenyl or any other analogous halophenyl radical, lower alkoxy phenyl, e.g. methoxyphenyl, ethoxyphenyl, butoxyphenyl or any other analogous lower alkoxyphenyl radical, cyanophenyl, nitrophenyl, trifluoromethylphenyl, lower alkylmercaptophenyl, e.g. methylmercaptophenyl, butylmercaptophenyl or any other analogous lower alkylmercaptophenyl radical, lower alkylsulfinylphenyl, e.g. methylsulfinylphenyl, propylsulfinylphenyl or any other analogous lower alkylsulfinylphenyl radical, lower alkylsulfonylphenyl, e.g. methylsulfonylphenyl, ethylsulfonylphenyl, hexylsulfonylphenyl or any other lower alkylsulfonylphenyl radical, N-acylaminophenyl, such as N-lower alkanoylaminophenyl, e.g. N-acetylaminophenyl, Nbutyrylaminophenyl as well as N-benzoylaminophenyl or any other analogous N-acylaminophenyl radical, N,N-di-lower alkylaminophenyl, e.g. N,N-dimethylaminophenyl, N- methyl-N-ethylaminophenyl or any other analogous N,N- di-lower alkylaminophenyl radical, or any equivalent substituted phenyl radical. Substituents on the phenyl group must be of a nature that they are not reactive with the isocyanate and among such groupings those skilled in the art will recognize are amino, hydroxy, carboxy and mercapto.

The substituents on the phenyl radical above enumerated do not materially alfect adversely the utility hereinbefore asserted for the unsubstituted-phenyl compound.

The benzene ring can be replaced by equivalent polycyclic aromatic rings e.g. l-naphthyl, Z-naphthyl or substituted l-naphthyl or substituted Z-naphthyl wherein one or more of the same or different substituents may be attached to any of the available positions. Moreover the benzene ring can be replaced by equivalent heterocyclic anomatic rings, e.g. pyridyl, furyl, thienyl, isoquinolyl, quinolyl, thiazolyl, pyrimidyl or these groups containing additional substituents, e.g. lower alkyl, lower-alkoxy, halo or other substituents.

The compounds of this invention can be used in the form of compositions for oral or parenteral use which contain the compounds in admixture with an organic or inorganic solid or liquid carrier. The compositions can be in the form of tablets, lozenges, capsules, dragees, pills, powders and aqueous and non-aqueous solutions or suspensions. In preparing such compositions there can be used for example carriers such as water, gelatin, sugars, e.g. lactose and sucrose, starches, cellulose derivatives, talc, stearic acid, magnesium stearate, gums, vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil and corn oil, propylene glycol, polyalkylene glycols, alginic acid or any other known carrier used for such preparations. The compositions can contain auxiliary substances, such as preserving, stabilizing, emulsifying, coloring, flavoring and wetting agents, buffers, etc.

We claim:

1. 4-imino-3-R-2-oxoimidazolidine-l-acetonitrile wherein R is phenyl or phenyl substituted by lower alkyl, halo, lower alkoxy, cyano, nitro, trifluoromethyl, lower alkylmercapto, lower alkylsulfinyl, lower alkylsulfonyl, lower alkanoyl, lower alkanoylamino, benzoylamino and dilower-alkylamino.

2. A compound according to claim 1 wherein R is halophenyl.

3. 4 imino-3-(4-chlorophenyl)-2-oxoimidazolidine-1- acetonitrile according to claim 2 wherein R is 4-chlorophenyl. J

References Cited FOREIGN PATENTS 629,779 10/1963 Belgium.

HENRY R. JILES, Primary Examiner N. TROUSOF, Assistant Examiner U.S. Cl. X.R. 260-453, 465, 999

' Patent "No j, 46}, 787

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Dated August 26, 1969 Invent-(3) Frederick K. Kirchner and Andrew W. Zalay It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 1, line 52, "Iminodiacetonitraile" should read --Im1nod1aceton1tr1le--. Column 4, line 16, "iminodiacetontrl should read --iminodiacetonitrile--; lines 67-68, "B-(H-bromophenyl) 4-imino-2-oxo1m1dazol 1d1ne" should read --3-(4-bromophenyl)-4-1mino-2-oxoimidazol1dine-1-aceton1tr1le-- Column 5, line 73, "descirbed" should read --descr1bed--; line 7 4, "islation" should read --1solat1'on--. Column 6, line 13, "by a reaction" should read --by the reaot1on-; line 21, "...(4-acet phenyl)urea" should read (h-acetylphenyl urea"; line 36, "descirbed" should read --descr1bed--.

SIGNED AND SEALED MAY 2 e 1970 (SEAL) Amau' EdwmiMFletcher, J WILLIAM E. saHuYmR, JR- .Attesting Officer Gomissianar of Patents 

